Dengue virus (DEN) causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent arthropod-borne viral illnesses in humans worldwide. Studies suggest that DHF/DSS is an immunopathogenic disease in which the T cell-mediated immune system may be dysregulated. However, the precise role of the T cell-dependent immunity in response to DEN infection in vivo is not fully defined due to the lack of an adequate animal model that allows dissection of the adaptive immune response. Our long-term goal is to elucidate how the immune system interacts with DEN in vivo and then develop a mouse model of DHF/DSS. In this proposal, we will test the hypothesis that T cells play a protective role in the host response to DEN. Specifically, we will characterize the T cell response to primary DEN infection in mice by monitoring T cell proliferation and differentiation and by identifying the DEN epitopes recognized by CD4+ and CD8+ T cells (Aim 1). Next, we will determine whether T cells can protect against primary DEN infection using a variety of loss-of-function and gain-of-function models for mouse T cells in combination with newly generated DEN strains that cause disease in 100% of T and B cell-deficient mice, and are nonvirulent in wild-type mice (Aim 2). Overall, this research will elucidate the cellular mechanisms of the immune response to primary DEN infection in vivo and establish the foundation for elucidating the protective versus pathogenic mechanisms of the immune system in primary and sequential DEN infections. [unreadable] [unreadable] [unreadable] [unreadable]